Abstract

Stereoselective metabolism of cibenzoline succinate, an oral antiarrhythmic drug, was investigated on hepatic microsomes from humans and rats and microsomes from cells expressing human cytochrome P450s (CYPs). Four main metabolites, M1 (p-hydroxycibenzoline), M2 (4,5-dehydrocibenzoline), and unknown metabolites M3 and M4, were formed by human and rat liver microsomes. The intrinsic clearance (CL_int) of the M1 formation from R(+)-cibenzoline was 23-fold greater than that of S(−)-cibenzoline in human liver microsomes, whereas the R(+)/S(−)-enantiomer ratio of CL_int for M2, M3, and M4 formation was 0.39 to 0.83. The total CL_int for the formation of the four main metabolites from S(−)- and R(+)-cibenzoline was 1.47 and 1.64 μl/min/mg, respectively, suggesting that the total CL_int in R(+)-enantiomer was slightly greater than that in S(−)-enantiomer in human liver microsomes. The M1 formation from R(+)-cibenzoline was highly correlated with bufuralol 1′-hydroxylation and CYP2D6 content and was inhibited by quinidine, a potent inhibitor of CYP2D6. Additionally, only microsomes containing recombinant CYP2D6 were capable of M1 formation. These results suggest that the M1 formation from R(+)-cibenzoline was catalyzed by CYP2D6. The formation of M2, M3, and M4 from S(−)- andR(+)-cibenzoline was highly correlated with testosterone 6β-hydroxylation and CYP3A4 content. Ketoconazole, which is a potent inhibitor of CYP3A4/5, had a strong inhibitory effect on their formation, and the M4 formation from R(+)-cibenzoline was inhibited by quinidine by 45%. The formation of M2 was also inhibited by quinidine by 46 to 52% at lower cibenzoline enantiomers (5 μM), whereas the inhibition by quinidine was not observed at a higher substrate concentration (100 μM). In male rat liver microsomes, ketoconazole and quinidine inhibited the formation of the main metabolites, M1 and M3, >74% and 44 to 59%, respectively. These results provide evidence that CYP3A and CYP2D play a major role in the stereoselective metabolism of cibenzoline in humans and male rats.